The present invention is directed to a method for treatment of cardiovascular injuries where plaque formation is present. The method involves administering an angiogenesis inhibitor to the plaque.
Cardiovascular ailments are a significant problem in society. Individuals afflicted with them can have decreased mobility, can require prolonged administration of drugs and the conditions can lead to death. These ailments can include atherosclerosis, restenosis, thrombosis, myocardial infarction, coronary heart disease, stroke, and other diseases.
Atherosclerosis is a common form of arteriosclerosis that results from the development of an intimal lesion and subsequent narrowing of the vessel lumen. As the lesions increase in size, they reduce the diameter of the arteries and impede blood circulation. The formation of the atherosclerotic lesion is typically classified in five overlapping stagesxe2x80x94(1) migration of smooth muscle cells, (2) lipid accumulation, (3) recruitment of inflammatory cells, (4) proliferation of vascular smooth muscle cells, and (5) extracellular matrix deposition. In a healthy vessel, the vast majority of the smooth muscle cells are contained in the vessel media. As lesions develop, smooth muscle cells migrate from the media to the intima of the vessel. Although smooth muscle cells in healthy vessel walls do not significantly accumulate lipid, the intimal smooth muscle cells have an increased capacity for lipid uptake and storage. One model of lesion progression proposes that macrophages are attracted to the lipid accumulating in the lesions in order to remove the lipid from the vessel wall. Moreover, the intimal smooth muscle cell accumulation is typically accompanied by medial thinning. These lesions are also rich in extracellular matrix deposition, particularly collagen fibers.
In some advanced lesions, new capillaries grow into the inner intimal layer of the plaque. The vasa vasorum are small nutrient arteries and veins found in the media and adventitia of larger blood vessels. In vessels containing artherosclerotic lesions, this microvascular network can become more abundant and extend into the intima (sometimes referred to here as plaque vessels or intimal vessels).
There are presently a number of methods for treating atherosclerosis, which include both surgical and medical treatment. The therapy that is presently preferred is percutaneous translumenal coronary angioplasty (xe2x80x9cPTCAxe2x80x9d, commonly referred to as xe2x80x9cballoon angioplastyxe2x80x9d). In this procedure, a catheter equipped with an inflatable balloon is threaded intravascularly to the site of the atherosclerotic narrowing of the vessel. By inflating the balloon, the plaque enlarging the vessel is compressed, thereby reducing the obstruction and improving coronary flow. Thus, this procedure is widely used in patients with coronary artery disease, particularly to relieve myocardial ischemia.
While the initial success appears high, complications can frequently develop. For example, stenosis following this procedure remains a significant problem with a significant number of patients, in some studies up to one-third of the patients, developing restenosis within one to three months.
Restenosis refers to the renarrowing of an artery after initially successful angioplasty. Restenosis of the blood vessel is thought to be due to injury to the endothelial cells of the blood vessel during angioplasty or during the inflation of the balloon catheter. During recovery after surgery, smooth muscle cells proliferate faster than endothelial cells narrowing the lumen of the blood vessel and narrowing the atherosclerotic process anew. Accordingly, in recent years such smooth muscle cell proliferation has been recognized as a major clinical problem limiting the effectiveness of percutaneous translumenal coronary angioplasty.
There have been numerous attempts to deal with this problem. For example, using a double balloon catheter for regional delivery of a therapeutic agent at the angioplasty site, such as heparin. Another approach has been to place endovascular stents in the dilated segments to mechanically block abrupt closure and restenosis. However, the use of such stents is limited by direct (subacute thrombosis) or indirect (bleeding, peripheral vascular complications) complications. Other approaches include treating the patient with anticoagulant and/or antiplatelet agents during the recovery period.
Recently the use of angiogenic agents has been proposed to assist in recovery. See e.g. U.S. Pat. No. 5,830,879. This patent teaches that by using an angiogenic agent, such as vascular endothelial growth factor (VEGF), smooth muscle cell proliferation is indirectly inhibited by the agent, directly facilitating reendothelization of the injured vessel. Angiogenic agents have also been proposed for treatment of other vascular problems. However, the long-term prognosis of the patients treated by this approach is not known. For example, published studies have demonstrated that delivery of endothelial cell growth factors, such as VEGF and members of the FGF family (FGF-1, FGF-2), to the vessel wall have been accompanied by increased intimal thickening at the site of vascular balloon injury. (Lazarous, D. F., Circulation 94: 1074-82, 1996; Nabel, E. G., Nature 362: 844-6, 1993). Accordingly, the need for other methods to reduce problems associated with artherosclerosis and angiogenesis remain. In addition, patients with current malignancies and retinal neovascularization are currently ineligible for treatments with angiogenic agents, but may be appropriate candidates to receive angiogenesis inhibitors.
We have now discovered that by delivering angiogenesis inhibitors to patients having coronary diseases where there is an increase in plaque vessels, we can inhibit plaque growth and reduce intimal neovascularization and inhibit lesion severity.
The angiogenesis inhibitor can be delivered by using the agent itself or a nucleic acid segment encoding the appropriate agent. The angiogenesis inhibitor can be selected from the group consisting of fumagillin derivatives such as O-chloracetyl-carbamoylfumagillol (sometimes called AGM-1470 or TNP-470), endostatin (a C terminal 20 kd fragment of the basement membrane protein Collagen XVIII; Ingber, B., et al., Nature 348: 555-7, 1990; Boehm, T., et al., Nature 390, 404-7, 1997; O""Reilly, M. S., et al., Cell 88: 277-85, 1997), angiostatin, platelet factor 4, vasostatin, interferon-xcex1 and -xcex2 (IFN), thalidomide, thrombospondin peptides, etc. TNP-470 and endostatin are preferred.
In this method one selects an individual showing signs of a coronary vascular problem such as formation of an atherosclerotic lesion. Preferably one screens the individual for an assessment of plaque vessel growth, unstable clinical symptoms, or evidence of increased neovascularization in atherosclerotic lesions. We have found that it is the unstable plaque vessels that can cause the greatest trauma to the individual. The plaques can be determined by looking at the degree of neovascularization or evidence of intramural hemorrhage or for the presence of inflammatory cells. We believe capillaries in the intimal layer of atherosclerotic lesions are permeable and mechanically weak, which predisposes them to bleed. The degree of neovascularization in atherosclerotic lesions is correlated with areas of high inflammatory cell content. Areas of inflammatory cells in some lesions are sites of mechanical weakness and correspond to sites of plaque rupture, which trigger thrombosis in the artery and give rise to heart attacks, strokes and vascular occlusion (Burke, A. P., New Engl. J. Med. 336:1276-82,1997).
Although the capillaries within atherosclerotic lesions are too small to be detected by conventional angiography, the detection of intimal neovascularization in atherosclerotic lesions may be accomplished by known methods such as magnetic resonance imaging with contrast agents that show enhancement in tissues with increased perfusion and permeability; nuclear scintigraphy of lesions that show accumulation of technetium-99m labeled agents that target endothelial cells and/or inflammatory cells in lesions; and by intravascular, duplex, and conventional ultrasound used in conjunction with blood contrast agents (Vallabhajosula, S., J., Nuclear Med 38: 1788-96, 1997). Newly developed technologies such as optical coherence tomography (OCT) and infrared or rahman spectroscopy can be enhanced to detect target molecules associated with the endothelial cells that comprise plaque neovascularization or evidence of hemorrhage around the neovascularization in the plaque.
Looking at plaque thickness is an alternative for screening for unstable plaques. In our studies, we found that increased plaque thickness beyond 250 microns, or about 0.3 mm thickness, was associated with a 9-fold increased prevalence of intimal neovascularization in atherosclerotic lesions in mice. This dimension is observed in human atherosclerotic lesions also (Geiringer, E., J. Pathol. Bact. 63: 210-11, 1951). Another criteria is measuring the intima area to total wall area of the plaque, by intravascular ultrasound for example. If the area ratio is at least 0.4, preferably about 0.5, more preferable 0.54 or greater, then the plaque is considered potentially unstable and the individual is selected for treatment.
After an individual is selected, the individual is treated by administration of the angiogenesis inhibitor. In one embodiment one administers a nucleic acid sequence encoding an angiogenesis inhibitor, instead of the agent.
The plaque may be contacted with the agent by any means of administration. For example, subcutaneous injection of the agent, oral administration, or injection by a catheter or needle. One preferred method is by use of standard catheter delivery systems to bring the agent to the general region where the plaque is present. These methods include use of balloon catheter, porous balloon catheter, and a hydrophilic polymer coated balloon such as a hydrogel polymer coated balloon.
The term xe2x80x9ceffective amountxe2x80x9d means the amount necessary on the part of the agent or the nucleic acid delivered to the plaque cells in the lesion to inhibit plaque growth.